RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia

Ren，Jian Gang1,2,3; Xing，Bowen2,3; Lv，Kaosheng2,3,4; O’Keefe，Rachel A.5; Wu，Mengfang2,3; Wang，Ruoxing2,3; Bauer，Kaylyn M.6; Ghazaryan，Arevik6; Burslem，George M.7; Zhang，Jing8; O’Connell，Ryan M.6; Pillai，Vinodh9; Hexner，Elizabeth O.10; Philips，Mark R.5; Tong，Wei2,3

2023-06-15

10.1172/JCI165510

Journal of Clinical Investigation   Impact Factor & Quartile

0021-9738

1558-8238

RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

SCI

English

NI Journal Papers

Others

National Institutes of Health[R01CA152108];National Institutes of Health[R01CA163489];National Institutes of Health[R01CA271523];National Institutes of Health[R01DK127738];National Institutes of Health[R35CA253178];

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001022654700006

AMER SOC CLINICAL INVESTIGATION INC

CLINICAL MEDICINE

2-s2.0-85161985387

Scopus

1.State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST),Key Laboratory of Oral Biomedicine,Ministry of Education,School and Hospital of Stomatology,Wuhan University,Wuhan,Hubei,China
2.Division of Hematology,Children’s Hospital of Philadelphia,Philadelphia,United States
3.Department of Pediatrics,Perelman School of Medicine,The University of Pennsylvania,Philadelphia,United States
4.Department of Biochemistry,School of Medicine,The Southern University of Science and Technology,Shenzhen,Guangdong,China
5.Department of Medicine,Perlmutter Cancer Center,New York University Grossman School of Medicine,New York,United States
6.Department of Pathology,University of Utah,Salt Lake City,United States
7.Department of Biochemistry and Biophysics,Perelman School of Medicine,University of Pennsylvania,Philadelphia,United States
8.McArdle Laboratory for Cancer Research,University of Wisconsin–Madison,Madison,United States
9.Pathology and Laboratory Medicine,Children’s Hospital of Philadelphia,Philadelphia,United States
10.Division of Hematology and Oncology,Abramson Cancer Center,University of Pennsylvania,Philadelphia,United States

Ren，Jian Gang,Xing，Bowen,Lv，Kaosheng,et al. RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia[J]. Journal of Clinical Investigation,2023,133(12).

Ren，Jian Gang.,Xing，Bowen.,Lv，Kaosheng.,O’Keefe，Rachel A..,Wu，Mengfang.,...&Tong，Wei.(2023).RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia.Journal of Clinical Investigation,133(12).

Ren，Jian Gang,et al."RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia".Journal of Clinical Investigation 133.12(2023).